Abstract
Antibody immunity against malaria is effective but non-sterile. In addition to antibody-mediated inhibition, neutralisation or opsonisation of malaria parasites, antibody-mediated complement activation is also important in defense against infection. Antibodies form immune complexes with parasite-derived antigens that can activate the classical complement pathway. The complement system provides efficient surveillance for infection, and its activation leads to parasite lysis or parasite opsonisation for phagocytosis. The induction of complement-fixing antibodies contributes significantly to the development of protective immunity against clinical malaria. These complement-fixing antibodies can form immune complexes that are recognised by complement receptors on innate cells of the immune system. The efficient clearance of immune complexes is accompanied by complement receptor internalisation, abrogating the detrimental consequences of excess complement activation. Here, we review the mechanisms of activation of complement by alternative, classical, and lectin pathways in human malaria at different stages of the Plasmodium life cycle with special emphasis on how complement-fixing antibodies contribute to protective immunity. We briefly touch upon the action of anaphylatoxins, the assembly of membrane attack complex, and the possible reasons underlying the resistance of infected erythrocytes towards antibody-mediated complement lysis, relevant to their prolonged survival in the blood of the human host. We make suggestions for further research on effector functions of antibody-mediated complement activation that would guide future researchers in deploying complement-fixing antibodies in preventive or therapeutic strategies against malaria.
Highlights
TO MALARIAMalaria remains one of the major causes of severe morbidity and mortality globally
Severe malaria often manifests as severe anaemia, Antibody-Dependent Complement Activation in Malaria cerebral malaria or acute lung or kidney injury, Lung or kidney injury may lead to pulmonary oedema or renal failure, which is less common in children than adults [reviewed in [3]]
Passive transfer studies of a modified monoclonal antibody against PfRh5 (P. falciparum reticulocyte homologue 5) indicate that neutralising antibody alone requires high titres [97], indicating a role for Fc-mediated antibody function. This may not, be directly attributable to complement fixation as studies of vaccine-induced immunity suggested that NK cell and Fc receptor engagement rather than complement fixation were independent correlates of protection [10]
Summary
Malaria remains one of the major causes of severe morbidity and mortality globally. In 2019 alone, there were 229 million clinical episodes of malaria causing 0.4 million deaths. In people living in malaria-endemic areas, immunity to malaria is gradually acquired following repeated exposure so that over time individuals become relatively protected from malaria and its complications [reviewed in [6]]. This naturally acquired immunity was demonstrated to be antibody-mediated, when antibodies transferred from apparently immune adults to young children with clinical malaria were able to reduce parasite densities [7]. We focus on the importance of understanding the roles of antibody-mediated complement activation in these different stages of the Plasmodium life cycle, together with the mechanisms that parasites adopt to evade complement attack to promote their survival. A deeper understanding of antibodymediated complement activation across the Plasmodium life cycle will provide insights into harnessing complement activation in antibody-mediated protection in malaria
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